Molecular Mechanisms Mediating Resistance to Leptin Signaling During Fat Gain

脂肪增加期间调节瘦素信号传导抵抗的分子机制

• 批准号: 7587786
• 负责人: Virend K Somers
• 金额: $ 22.67万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7587786
• 关键词: Abdomen; Address; Adipocytes; Adipose tissue; Adult; Arts; Biochemical; Biochemistry; Blood Vessels; Body Weight Changes; Body Weight decreased; Body fat; Cardiovascular Diseases; Caveolae; Child; Development; Diet; Disruption; Eating; Endothelium; Energy Metabolism; Equilibrium; Failure; Fatty acid glycerol esters; Feedback; Histology; Human; In Vitro; Lead; Leptin; Leptin resistance; Lipids; Mediating; Membrane Microdomains; Modeling; Molecular; Molecular Biology; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Obesity; Peripheral; Phase; Play; Prevalence; Proteins; Protocols documentation; Public Health; Resistance; Risk; Risk Factors; Role; Satiation; Series; Serum; Signal Transduction; Staging; Testing; Therapeutic; Therapeutic Intervention; United States; Vasodilation; Weight Gain; attenuation; caveolin 1; frontier; human FAT protein; human NOS3 protein; human subject; interest; leptin receptor; novel; prevent; protein expression; response

DESCRIPTION (provided by applicant): Obesity is associated with increased risk for the development of type 2 diabetes mellitus and cardiovascular disorders. New frontiers in therapeutic intervention against obesity lie in the recognition of novel mechanisms involved during the initial stages of weight gain in humans. There has been increasing interest in the role leptin, a peripheral circulating satiety factor, which plays a key role in balancing energy expenditure and preventing fat gain. However, leptin is found at higher levels in obese humans than in non-obese humans. The failure of elevated leptin to elicit weight loss in common forms of human obesity suggests the attenuation of leptin action (leptin resistance). To this end, we propose a novel hypothesis that resistance to leptin signaling is a result of molecular and structural changes in caveolar membrane microdomains. To test our hypothesis we propose a series of studies directed at investigating the molecular mechanisms involved in disruption of leptin signaling during weight gain, using abdominal adipose tissue obtained from healthy human subjects who gain body fat in response to an overfeeding protocol. We also propose to investigate the reversibility of these changes during fat loss. In our preliminary studies we have observed first, increases in circulating leptin levels during weight gain accompanied by decreased endothelium mediated vasodilation and increased adipocyte fat accumulation. Second, increases in caveolin-1 and endothelial nitric oxide synthase (eNOS) expression during weight gain and reversal of these changes during weight loss. Third, increases in leptin-dependent caveolin-1 expression in vitro. Fourth, the ability of caveolin-1 to inhibit leptin signaling in-vitro. These observations point to a probable role of caveolin-1 and caveolar microdomains in disruption of leptin signaling as a feedback mechanism in response to high leptin levels. In this proposal we will combine histological and molecular biologic approaches to study the morphological and compositional changes in caveolar membrane microdomains associated with weight gain and weight loss (AIM#1), and the role of caveolin-1 during weight gain and weight loss in adipocytes and adipose tissue microvasculature (AIM#2). We hypothesize that during weight gain, increased circulating leptin leads to increased caveolin-1 expression in adipose tissue, which in turn leads to increased caveolin-1 and Ob-R interaction in the caveolar microdomains. This increased interaction may result in disruption of downstream Ob-R signaling which would then lead to leptin resistance. Attenuation of leptin signaling will result in increased lipid accumulation and decreased eNOS activity. The uniqueness and translational strength of this proposal lies in studying at the molecular level dynamic weight changes in human subjects, and in our ability to differentially study them in adipocytes and adipose tissue microvessels along with in-vitro studies. The long term significance of the proposal will be in understanding the mechanisms involved in attenuation of leptin signaling during weight gain in human subjects and its reversibility during weight loss. This understanding would be pivotal in development of therapeutics related to leptin resistance and obesity. PUBLIC HEALTH RELEVANCE: The proposed studies will have clear and important implications regarding the molecular mechanisms involved in attenuation of leptin signaling during weight gain and its reversibility during weight loss. In addition the results of our proposed studies may be critical in development of therapeutics relating to leptin resistance and obesity.

描述（由申请人提供）：肥胖与2型糖尿病和心血管疾病的发展风险增加有关。对肥胖症的治疗干预的新领域在于人们认识到人类体重增加的最初阶段所涉及的新机制。对瘦素的作用是一种越来越多的兴趣，瘦素是外围循环元素，在平衡能量消耗和防止脂肪增加方面起着关键作用。然而，肥胖人的水平比非肥胖人更高。瘦素升高引起人类肥胖的体重减轻的失败表明瘦素作用的衰减（瘦素抗性）。为此，我们提出了一个新的假设，即对瘦素信号传导的耐药性是洞穴膜微区分子和结构变化的结果。为了检验我们的假设，我们提出了一系列研究，该研究旨在研究体重增加过程中瘦素信号破坏的分子机制，使用从健康的人类受试者获得的腹部脂肪组织，这些受试者从健康的人类受试者中获得，这些受试者响应过度喂养方案而获得体内脂肪。我们还建议研究脂肪流失期间这些变化的可逆性。在我们的初步研究中，我们首先观察到，体重增加期间循环瘦素水平的升高伴随着内皮介导的血管舒张降低和脂肪细胞脂肪的积累增加。其次，在体重增加和体重减轻期间这些变化的逆转过程中，小窝蛋白-1和内皮一氧化氮合酶（ENOS）的表达增加。第三，体外瘦素依赖性小窝蛋白-1表达的增加。第四，小窝蛋白-1抑制瘦素信号传导的能力。这些观察结果表明，小窝蛋白-1和小窝微域在破坏瘦素信号传导中的可能作用可能是响应高瘦素水平的反馈机制。在该提案中，我们将结合组织学和分子生物学方法，以研究与体重增加和体重减轻（AIM＃1）相关的洞穴膜微区域的形态和组成变化，以及小窝蛋白-1在脂肪细胞体重增加和体重减轻中的作用（AIM＃2）。我们假设在体重增加期间，循环瘦素增加会导致脂肪组织中的小窝蛋白-1表达增加，这又导致小窝微区域中的小窝蛋白-1和OB-R相互作用增加。这种增加的相互作用可能导致下游OB-R信号的破坏，从而导致瘦素耐药性。瘦素信号的衰减将导致脂质积累增加和eNOS活性降低。该提案的独特性和翻译强度在于研究人类受试者的分子水平动态权重变化，以及我们在脂肪细胞和脂肪组织微血管中差异化研究的能力以及视野内研究。该提案的长期意义将是了解人类受试者体重增加期间瘦素信号衰减的机制及其在体重减轻期间的可逆性。这种理解对于与瘦素耐药性和肥胖有关的治疗剂的发展至关重要。 公共卫生相关性：拟议的研究将对体重增加期间瘦素信号衰减及其在体重减轻期间的可逆性期间所涉及的分子机制具有明显的重要意义。此外，我们提出的研究的结果对于与瘦素耐药性和肥胖有关的治疗剂的发展可能至关重要。